Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading sources of cancer mortality worldwide. An initial response to chemotherapy, such as gemcitabine (GEM) alone or in combination with other chemotherapies, is often followed by emergent resistance, underscoring the urgent need for targeted therapies. PDAC cells are highly addicted to oncogenic K-RAS mutations for their growth, progression, immunosuppression, and drug resistance, but mutant K-RAS in PDAC is still challenging to target. A N-glycosylation inhibitor, tunicamycin (TM), is a potent killer of PDAC cells. However, the free TM is very toxic in clinical settings. We developed a pH/hypoxia-responsive iRGD-tagged biodegradable nano-encapsulated TM (NPTM) that overcomes the limitations of free TM and shows promising results in inhibiting PDAC cell growth via apoptosis. The NPTM has shown significant promise, reducing cellular heterogeneity, drug resistance, in vitro desmoplasia, and subcutaneous tumor growth and markedly prolonging the survival in a KPC-xenograft mouse model. The studies suggest that TM targets K-RasG12D-dependent multiple signaling pathways such as EIF4E, STAT3, and STAT5 activities and CCN1 to promote its anticancer efficacy. Together, these studies reveal the potential of simultaneously targeting a K-RasG12D-dependent signal and CCN1 with first-line chemotherapy and provide a rationale for future clinical testing of NPTM for PDAC therapy.
